tbuckley/cabot-search huggingface dataset:
Ultrawide-field En face OCT of Multiple Evanescent White Dot Syndrome
Authors: Jialiang Duan, Huihui Qi, Qingli Shang
Journal: Ophthalmology (2023)

A 36-year-old woman diagnosed with multiple evanescent white dot syndrome (MEWDS) underwent a multimodal imaging examination. Autofluorescence (A) and indocyanine green angiography (B) were consistent with typical MEWDS features. Additionally, en face OCT image (at the level of the outer retina) (C) obtained from ultrawide-field swept-source OCT angiography revealed small hyperreflective dots around the optic nerve and confluent hyperreflective spots disseminated at the midperipheral retina. The OCT B-scan (D) confirmed multiple hyperreflective dots (yellow arrows) that corresponded with the findings on the en face OCT.
Tailoring the multiscale mechanics of tunable decellularized extracellular matrix (dECM) for wound healing through immunomodulation
Authors: Pu Luo, Ruoxuan Huang, You Wu, Xingchen Liu, Zhengjie Shan, Li Gong, Shudan Deng, Haiwen Liu, Jinghan Fang, Shiyu Wu, Xiayi Wu, Quan Liu, Zetao Chen, Kelvin W.K. Yeung, Wei Qiao, Shoucheng Chen, Zhuofan Chen
Journal: Bioactive Materials (2023)

With the discovery of the pivotal role of macrophages in tissue regeneration through shaping the tissue immune microenvironment, various immunomodulatory strategies have been proposed to modify traditional biomaterials. Decellularized extracellular matrix (dECM) has been extensively used in the clinical treatment of tissue injury due to its favorable biocompatibility and similarity to the native tissue environment. However, most reported decellularization protocols may cause damage to the native structure of dECM, which undermines its inherent advantages and potential clinical applications. Here, we introduce a mechanically tunable dECM prepared by optimizing the freeze-thaw cycles. We demonstrated that the alteration in micromechanical properties of dECM resulting from the cyclic freeze-thaw process contributes to distinct macrophage-mediated host immune responses to the materials, which are recently recognized to play a pivotal role in determining the outcome of tissue regeneration. Our sequencing data further revealed that the immunomodulatory effect of dECM was induced via the mechnotrasduction pathways in macrophages. Next, we tested the dECM in a rat skin injury model and found an enhanced micromechanical property of dECM achieved with three freeze-thaw cycles significantly promoted the M2 polarization of macrophages, leading to superior wound healing. These findings suggest that the immunomodulatory property of dECM can be efficiently manipulated by tailoring its inherent micromechanical properties during the decellularization process. Therefore, our mechanics-immunomodulation-based strategy provides new insights into the development of advanced biomaterials for wound healing.
Engineering homologous platelet-rich plasma, platelet-rich plasma-derived exosomes, and mesenchymal stem cell-derived exosomes-based dual-crosslinked hydrogels as bioactive diabetic wound dressings
Authors: Bianza Moise Bakadia, Abeer Ahmed Qaed Ahmed, Lallepak Lamboni, Zhijun Shi, Biampata Mutu Mukole, Ruizhu Zheng, Mazono Pierre Mbang, Bi Zhang, Mario Gauthier, Guang Yang
Journal: Bioactive Materials (2023)

The management of diabetic wounds remains a critical therapeutic challenge. Platelet-rich plasma (PRP) gel, PRP-derived exosomes (PRP-Exos), and mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated therapeutic potential in wound treatment. Unfortunately, their poor mechanical properties, the short half-lives of growth factors (GFs), and the burst release of GFs and exosomes have limited their clinical applications. Furthermore, proteases in diabetic wounds degrade GFs, which hampers wound repair. Silk fibroin is an enzyme-immobilization biomaterial that could protect GFs from proteases. Herein, we developed novel dual-crosslinked hydrogels based on silk protein (SP) (sericin and fibroin), including SP@PRP, SP@MSC-Exos, and SP@PRP-Exos, to promote diabetic wound healing synergistically. SP@PRP was prepared from PRP and SP using calcium gluconate/thrombin as agonist, while SP@PRP-Exos and SP@MSC-Exos were derived from exosomes and SP with genipin as crosslinker. SP provided improved mechanical properties and enabled the sustained release of GFs and exosomes, thereby overcoming the limitations of PRP and exosomes in wound healing. The dual-crosslinked hydrogels displayed shear-induced thinning, self-healing, and eradication of microbial biofilms in a bone-mimicking environment. In vivo, the dual-crosslinked hydrogels contributed to faster diabetic wound healing than PRP and SP by upregulating GFs expression, down-regulating matrix metalloproteinase-9 expression, and by promoting an anti-NETotic effect, angiogenesis, and re-epithelialization. Hence, these dual-crosslinked hydrogels have the potential to be translated into a new generation of diabetic wound dressings.
Gut microbiome modified by bariatric surgery improves insulin sensitivity and correlates with increased brown fat activity and energy expenditure
Authors: Jitender Yadav, Tao Liang, Tairan Qin, Nayanan Nathan, Katherine J.P. Schwenger, Lauren Pickel, Li Xie, Helena Lei, Daniel A. Winer, Heather Maughan, Susan J. Robertson, Minna Woo, Wendy Lou, Kate Banks, Timothy Jackson, Allan Okrainec, Susy S. Hota, Susan M. Poutanen, Hoon-Ki Sung, Johane P. Allard, Dana J. Philpott, Herbert Y. Gaisano
Journal: Cell Reports Medicine (2023)

Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice. Mice colonized by FMT from patients' post-surgery stool exhibit significant changes in microbiota composition and metabolomic profiles and, most importantly, improved insulin sensitivity compared with pre-RYGB FMT mice. Mechanistically, mice harboring the post-RYGB microbiome show increased brown fat mass and activity and exhibit increased energy expenditure. Moreover, improvements in immune homeostasis within the white adipose tissue are also observed. Altogether, these findings point to a direct role for the gut microbiome in mediating improved metabolic health post-RYGB surgery.
Air pollution, EGFR mutation, and cancer initiation
Authors: Si-Chong Han, Gui-Zhen Wang, Guang-Biao Zhou
Journal: Cell Reports Medicine (2023)

Swanton et al.1 find that PM2.5 exposure is associated with EGFR/KRAS-driven lung cancer incidence. PM2.5 increases EGFR pre-mutated alveolar type II cell progenitor function and tumorigenic activity through interstitial macrophage-secreted IL-1β, providing potential prevention approaches to inhibit cancer initiation.
A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy
Authors: Luchen Sun, Nanfei Yang, Bing Chen, Yuncheng Bei, Zisheng Kang, Can Zhang, Nan Zhang, Peipei Xu, Wei Yang, Jia Wei, Jiangqiong Ke, Weijian Sun, Xiaokun Li, Pingping Shen
Journal: Acta Pharmaceutica Sinica B (2023)

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.
Intratumoral erythroblastic islands restrain anti-tumor immunity in hepatoblastoma
Authors: Yuanqi Wang, Xiao Xiang, Huadong Chen, Luyao Zhou, Shuling Chen, Guopei Zhang, Xiaofei Liu, Xuxin Ren, Juncheng Liu, Ming Kuang, Juan Jiang, Jinbiao She, Zhichong Zhang, Ruidong Xue, Hong Jiang, Ji Wang, Sui Peng
Journal: Cell Reports Medicine (2023)

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+ macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.
Local and long-distance organization of prefrontal cortex circuits in the marmoset brain
Authors: Akiya Watakabe, Henrik Skibbe, Ken Nakae, Hiroshi Abe, Noritaka Ichinohe, Muhammad Febrian Rachmadi, Jian Wang, Masafumi Takaji, Hiroaki Mizukami, Alexander Woodward, Rui Gong, Junichi Hata, David C. Van Essen, Hideyuki Okano, Shin Ishii, Tetsuo Yamamori
Journal: Neuron (2023)

The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections' local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain.
Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy
Authors: Stuart Hawtin, Cédric André, Géraldine Collignon-Zipfel, Simone Appenzeller, Bettina Bannert, Lea Baumgartner, Damian Beck, Claudia Betschart, Thomas Boulay, Hermine I. Brunner, Melanie Ceci, Jonathan Deane, Roland Feifel, Enrico Ferrero, Diego Kyburz, Frederique Lafossas, Pius Loetscher, Christina Merz-Stoeckle, Pierre Michellys, Barbara Nuesslein-Hildesheim, Friedrich Raulf, James S. Rush, Giulia Ruzzante, Thomas Stein, Samantha Zaharevitz, Grazyna Wieczorek, Richard Siegel, Peter Gergely, Tamas Shisha, Tobias Junt
Journal: Cell Reports Medicine (2023)

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases. Moreover, MHV370 abrogates B cell, plasmacytoid dendritic cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 blocks secretion of TLR7 responses, including cytokine secretion, B cell activation, and gene expression of, e.g., interferon-stimulated genes. In the NZB/W F1 mouse model of lupus, MHV370 halts disease. Unlike hydroxychloroquine, MHV370 potently blocks interferon responses triggered by specific immune complexes from systemic lupus erythematosus patient sera, suggesting differentiation from clinical standard of care. These data support advancement of MHV370 to an ongoing phase 2 clinical trial.
DuSFE: Dual-Channel Squeeze-Fusion-Excitation co-attention for cross-modality registration of cardiac SPECT and CT
Authors: Xiongchao Chen, Bo Zhou, Huidong Xie, Xueqi Guo, Jiazhen Zhang, James S. Duncan, Edward J. Miller, Albert J. Sinusas, John A. Onofrey, Chi Liu
Journal: Medical Image Analysis (2023)

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is widely applied for the diagnosis of cardiovascular diseases. Attenuation maps (μ-maps) derived from computed tomography (CT) are utilized for attenuation correction (AC) to improve the diagnostic accuracy of cardiac SPECT. However, in clinical practice, SPECT and CT scans are acquired sequentially, potentially inducing misregistration between the two images and further producing AC artifacts. Conventional intensity-based registration methods show poor performance in the cross-modality registration of SPECT and CT-derived μ-maps since the two imaging modalities might present totally different intensity patterns. Deep learning has shown great potential in medical imaging registration. However, existing deep learning strategies for medical image registration encoded the input images by simply concatenating the feature maps of different convolutional layers, which might not fully extract or fuse the input information. In addition, deep-learning-based cross-modality registration of cardiac SPECT and CT-derived μ-maps has not been investigated before. In this paper, we propose a novel Dual-Channel Squeeze-Fusion-Excitation (DuSFE) co-attention module for the cross-modality rigid registration of cardiac SPECT and CT-derived μ-maps. DuSFE is designed based on the co-attention mechanism of two cross-connected input data streams. The channel-wise or spatial features of SPECT and μ-maps are jointly encoded, fused, and recalibrated in the DuSFE module. DuSFE can be flexibly embedded at multiple convolutional layers to enable gradual feature fusion in different spatial dimensions. Our studies using clinical patient MPI studies demonstrated that the DuSFE-embedded neural network generated significantly lower registration errors and more accurate AC SPECT images than existing methods. We also showed that the DuSFE-embedded network did not over-correct or degrade the registration performance of motion-free cases. The source code of this work is available at https://github.com/XiongchaoChen/DuSFE_CrossRegistration.
Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers
Authors: Seid Muhie, Aarti Gautam, Ruoting Yang, Burook Misganaw, Bernie J. Daigle, Synthia H. Mellon, Janine D. Flory, Duna Abu-Amara, Inyoul Lee, Kai Wang, Ryan Rampersaud, Leroy Hood, Rachel Yehuda, Charles R. Marmar, Owen M. Wolkowitz, Kerry J. Ressler, Francis J. Doyle, Rasha Hammamieh, Marti Jett
Journal: Cell Reports Medicine (2023)

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.
Ketogenic diet protects MPTP‐induced mouse model of Parkinson's disease via altering gut microbiota and metabolites
Authors: Ziying Jiang, Xinyu Wang, Haoqiang Zhang, Jian Yin, Peiqing Zhao, Qingqing Yin, Zhenfu Wang
Journal: MedComm (2023)

Abstract The ketogenic diet (KD) is a low‐carbohydrate, high‐fat regime that is protective against neurodegenerative diseases. However, the impact of KD on Parkinson's disease (PD) and its mechanisms remains unclear. 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD was fed with KD for 8 weeks. Motor function and dopaminergic neurons were evaluated. Inflammation in the brain, plasma, and colon tissue were also measured. Fecal samples were assessed by 16S rDNA gene sequencing and untargeted metabolomics. We found that KD protected motor dysfunction, dopaminergic neuron loss, and inflammation in an MPTP mouse model of PD. 16S rDNA sequencing revealed that MPTP administration significantly increased Citrobacter , Desulfovibrio , and Ruminococcus , and decreased Dubosiella , whereas KD treatment reversed the dysbiosis. Meanwhile, KD regulated the MPTP‐induced histamine, N‐acetylputrescine, d ‐aspartic acid, and other metabolites. Fecal microbiota transplantation using feces from the KD‐treated mice attenuated the motor function impairment and dopaminergic neuron loss in antibiotic‐pretreated PD mice. Our current study demonstrates that KD played a neuroprotective role in the MPTP mouse model of PD through the diet–gut microbiota–brain axis, which may involve inflammation in the brain and colon. However, future research is warranted to explore the explicit anti‐inflammatory mechanisms of the gut–brain axis in PD models fed with KD.
Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicentre study
Authors: Pedro Puerta-Alcalde, Patricia Monzó-Gallo, Manuela Aguilar-Guisado, Juan Carlos Ramos, Júlia Laporte-Amargós, Marina Machado, Pilar Martin-Davila, Mireia Franch-Sarto, Isabel Sánchez-Romero, Jon Badiola, Lucia Gómez, Isabel Ruiz-Camps, Lucrecia Yáñez, Lourdes Vázquez, Mariana Chumbita, Francesc Marco, Alex Soriano, Pedro González, Ana Fernández-Cruz, Montserrat Batlle, Jesús Fortún, Jesús Guinea, Carlota Gudiol, Julio García, Maite Ruiz Pérez de Pipaón, Ana Alastruey-Izquierdo, Carolina Garcia-Vidal
Journal: Journal of Infection (2023)

ObjectivesWe describe the current epidemiology, causes, and outcomes of breakthrough invasive fungal infections (BtIFI) in patients with haematologic malignancies.MethodsBtIFI in patients with ≥ 7 days of prior antifungals were prospectively diagnosed (36 months across 13 Spanish hospitals) according to revised EORTC/MSG definitions.Results121 episodes of BtIFI were documented, of which 41 (33.9%) were proven; 53 (43.8%), probable; and 27 (22.3%), possible. The most frequent prior antifungals included posaconazole (32.2%), echinocandins (28.9%) and fluconazole (24.8%)—mainly for primary prophylaxis (81%). The most common haematologic malignancy was acute leukaemia (64.5%), and 59 (48.8%) patients had undergone a hematopoietic stem-cell transplantation. Invasive aspergillosis, principally caused by non-fumigatus Aspergillus, was the most frequent BtIFI with 55 (45.5%) episodes recorded, followed by candidemia (23, 19%), mucormycosis (7, 5.8%), other moulds (6, 5%) and other yeasts (5, 4.1%). Azole resistance/non-susceptibility was commonly found. Prior antifungal therapy widely determined BtIFI epidemiology. The most common cause of BtIFI in proven and probable cases was the lack of activity of the prior antifungal (63, 67.0%). At diagnosis, antifungal therapy was mostly changed (90.9%), mainly to liposomal amphotericin-B (48.8%). Overall, 100-day mortality was 47.1%; BtIFI was either the cause or an essential contributing factor to death in 61.4% of cases.ConclusionsBtIFI are mainly caused by non-fumigatus Aspergillus, non-albicans Candida, Mucorales and other rare species of mould and yeast. Prior antifungals determine the epidemiology of BtIFI. The exceedingly high mortality due to BtIFI warrants an aggressive diagnostic approach and early initiation of broad-spectrum antifungals different than those previously used.
Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity
Authors: Mingli Duan, Yurui Jia, Lifang Huo, Yiting Gao, Jia Wang, Wei Zhang, Zhanfeng Jia
Journal: Acta Pharmaceutica Sinica B (2023)

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
Wearable patches for transdermal drug delivery
Authors: Jiahui He, Yuyue Zhang, Xinge Yu, Chenjie Xu
Journal: Acta Pharmaceutica Sinica B (2023)

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.